CA1190933A

CA1190933A - Imidazolidine derivatives

Info

Publication number: CA1190933A
Application number: CA000420966A
Authority: CA
Inventors: Thomas Purcell
Original assignee: Synthelabo SA
Current assignee: Synthelabo SA
Priority date: 1982-02-05
Filing date: 1983-02-04
Publication date: 1985-07-23
Also published as: FR2521140A1; US4492709A; PT76196A; FR2521140B1; EP0086126A1; DK47683D0; PT76196B; JPS58146569A; IL67835A0; GR77414B; DE3360411D1; AU553893B2; EP0086126B1; ZA83763B; DK47683A; ATE14424T1; FI830397L; ES519532A0; AU1115083A; ES8403461A1

Abstract

ABSTRACT
"IMIDAZOLIDINE DERIVATIVES"

Imidazolidine derivatives of the formula:

wherein R1 represents the hydroxy radical and R2 represents a grouping -NHSO2CH3, -NHCOR' or -NHCONR'R", R' and R"
independently of one another representing a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or alternatively R2 represents the hydroxy radical and R1 represents a grouping -NHSO2CH3, -NHCOR' or ?NHCONR 'R", R' and R" independently of one another representing a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, and pharmacologically-acceptable acid addition salts thereof, are new therapeutically useful compounds. They are more particularly useful in the treatment of gastric hypersecretion or hyperacidity.

Description

DESCRIPTION
IIIMID~ZOLIDINE DERIVATIVES"

This invention relates to new therapeutically useful imidazolidine derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
The imidazolidine derivatives of the present invention are those compounds of the general formula:

wherein Rl represents the hydro~y radical and R2 represents a grouping -NHSO2CH3, -NHCOR' or ~HCONR'R'I, J R' and R" indepe!ndently of one another representing a hydrogen akom c,r an alkyl radical having from 1 to 4 carbon atoms, or alternatively R2 represents the hydroxy radical and Rl represents a grouping -~HSO2CH3, -~HCOR' or -NHCONR'R", Rl and R'' independently of 15 one anokher representing a hydrogen atom or an alkyl radical havi.ng f rom 1 to 4 carbon atoms, and their pharmacologically-acceptable acid addition salts.

The tautomeric forms of the compounds of general formula (I) are part of the present invention.
The preferred compounds are those wherein ~1 in general formula (I) represents the hydroxy radical, 5 and more particularly those wherein ~2 represents the grouping -NHC~O, -NHS02CH3 or -NHCONH2, and pharmacologically~acceptable acid addition salts thereof. The most preferred compound of the present invention is 2-(3--formylamino-4-hydroxyphenyl~nino)-10 imidazolidine.
According to a feature of the present invention, those imidazolidine derivatives of general formula (I) wherei.n ~1 represents the hydroxy radical are prepared by the process illustrated in the 15 following reaction scheme:-HO~ ~~C~I S~/ ~ ~,~N53<ENN~
(II) (III) (IV) H H

HO~ ~ ~ H2/Pd-C,~N~< ?

(VI ) \ H (V) N

~ ='< N

HO~

( IA ) wherein R~ is as hereinbefore deined when Rl is the hydroxy radical.
According to the reaction scheme, p-hydroxyaniline is reacted with 2-methylthioimidazoline 5 (optionally in the form of an acid addition salt such as the hydrochloride), for example in an organic solvent such as pyridine, to give 2-(4-hydroxyphenylimino)-imidazolidine, which is nitrated with nitric acid to give 2-(4~hydrox~-3-nitrophenylimino)-imidazolidine 10 this compound (formula V) is hydrogenated in the presence of a hydrogenation catalyst, such as palladium-on-charcoal, to give 2-(3-amino-4-hydroxyphenylimino)-imidazolidine, which is reacted with formic acid in the presence of acetic anhydride, or with methyl-15 sulphonyl chlori.de, or with a compound ~a~C0 or R'NC0(wherein R' represents an alk~l radical having from 1 to 4 carbon atom,s) to obtain an :imidazolidine derivative of general formula (IA).
According to a further feature of the present 20 invention, those imidazolidine derivatives of general formula (I) wherein R2 represents the hydroxy radical are prepared by the process illustrated in the following reaction scheme~-~ ClCOOC2H5 ~

H2~ HN o (VIII ) 0~
( VII ) H~03 ~H2 H /Pd-C ~N02 H~/\,/ HN/
~0 O (X) H (IX) CH3S~ HI
H (XI) H H

o~ (XII) ~/ OH tXIII) N
,~r~ H
Rl ~r OH
(IB) wherein Rl i5 as here:inbefore defined when R2 is the hydroxy radical.
~ ccording to the reaction scheme, o-aminophenol is reacted with ethyl chloroformate, the resulting 3H-5 benzoxazol 2-one obtained is nitrated with nitric acid, the nitro group of the resulting compolmd of ~ormula (IX) is reduced with hydrogen in the presence of a hydrogenation catalyst, such as palladium-on-charcoal, the 6-amino-3H-benzoxazol-2-one thus obtained is reacted 10 with 2-methylthioimidazoline, preferably in the form of an acid addition salt such as t:he hydroiodide, and the resulting compound of formula (XII~ is acidified to give 2-(4-amino-3-hydroxyphenylimino)-imidazolidine, which is reacted with formic acid in 15 the presence of acetic anhyride, or with methylsulphonyl chloride, or with a coimpound NaNCO or R'NCO (wherein R' represents an alkyl radical having from 1 to 4 carbon atoms) to obtain an imidazolidine derivative of general formula (IB).
Pharmacologically-acceptable acid addition salts of the imidazolidine derivative of general formula (I), e.g~ methanesulphonates, mandelates, fumarates, maleates, malonates, citrates, hydrochlorides, hydrobromides and hydroiodides, may be obtained by 25 methods known per se, f-or example by treatment of the imidazolidine base with the appropriate acid in a solvent medium, e.g~ an alkanol or ether, or mixtures thereof.

By the tenm 'methods known E~r se' as used in this specification is meant methods heretofore used or described in the literature.
The following Examples illustrate the 5 preparation of imidazolidine derivatives of general formula (I).
The analyses and the IR and N~ spectra confirm the structure of the compounds.
F~MPLE 1 -10 2-(3-Formylamino-4-hydroxyphenylimino)-imidazolidine and its hydrochloride.
(~1 = OH, R2 = -~HCHO) _ 1~ 2-(4-Hydroxyphenylimino)-imidclzolidine hydrochloride.
A mixture of 16.35 g (0.lS mo]) of 4-hydroxy-aniline and 38.4 g of 2--methylthioimidazoline hydrochloride in 150 cc of pyridine is heated at the reflux temperature for 2 hours. The thiol formed is trapped with KMnO4 in dilute sulphuric acid. After 20 standing overnight, the reaction mixture is poured into diethyl ether and washed with diethyl ether.
The mixture is taken up in ethanol~ Petroleum ether is added and the crystals formed are filtered off~

2-(4-Hydroxyphenylimino)-imidazolidine hydrochloride, 25 melting at 220-222C, is obtainedO

2. 2-(4-~ydroxy--3-nitrophenylimino)-imidazolidine hydrochloride.
13.25 g (0.0489 mol) of 2-(4-hydroxyphenyl-imino)-imidazolidine hydrochloride are introduced into 5 200 cc of acetic acid at ambient temperature, and

3.14 cc of nitric acid (specific gravity 1.42) are added. After 10 to 15 minutes the reaction mi~ture is poured into diethyl ether. After filtration and recrystallisation from ethanol, 2-(4-hydroxy-3-10 nitrophenylimino)-imidazolidine hydrochloride, melting at 231-233c,is obtained.
2-(3-Amino-4-hydroxyphenylimino)-imidaæolidine hydrochloride.
3.5 g of 2-(4-hydroxy-3-nitrophenylimino~-15 imidazolidine hydrochloride are hydrogenated in a Parr apparatus, under a pressure of 50 psi, in 80 cc of dimethylformamide in th,e presence as catalyst o~
10% palladium-on-charcoal.
After the catalyst has been removed, the 20 reaction mixture is poured into diethyl ether and the supernatant is decantedO After the addition of ethanol and petroleum ether to the residue, the crystals formed are filtered off to give 2-(3-amino-4-hydroxyphen~limino)-imidazolidine hydrochloride 25 melting at 217C.

3~3

4. 2-(3-Fonnylamino-4-hydroxyphenylimino)-imidazolidine hydrochloride.

5 cc of formic acid and 0.4 cc of acetic anhydride are introduced into a round-bottomed flask 5 and stirred for 15 minutes at 0C. 914 mg t4 m:illimols) of 2-(3-amino-4-hydroxyphenylimino)-imidazolidine hydrochloride are then added. The reaction m:ixture is stirred for 30 minutes and then poured into diethyl ether. The precipitate is 10 filtered off and recrystallised from a mixture of ethanol/petroleum ether. The hydrochloride of 2-(3-formylamino-4-hydroxyphenylimino)-imidazolidine, melting at 226C (decomposition), is thus obtained.

15 2-(3--Aminocarbonylamino-4-hydroxyphenylimino)-imidazolidine and its hydrochloride.
(Rl---OH, R2 = -~HCON~I2) 914 mg (4 millimols) of 2-(3-amino-4-20 hydroxyphenylimino)-imidazolidine hydrochloride (prepared as described in steps 1, 2 and 3 in Example 1) and 260 mg (~.32 millimols) of NaNCO are reacted together in a mixture of 6 cc of acetic acid and 4 cc of water. The reaction mixture is kept at 40C for Z5 1 hour. It is then evaporated to dryness and the residue is taken up in wa~er. The reaction mixture is J3~

- lQ -chromatographed on an Amberlite IRC 50 column. After evaporation, the residue is taken up in ethanol, and a mixture of diethyl ether/hydrochloric acid is added. After recrystallisation from ethanol, 5 2-(3-aminocarbonylamino-~-hydroxyphenylimino)-imidazolidine hydrochloride, melting at 227C
(decomposition), is obtained.

2-(4-Formylamino-3-hydroxyphenylimino~-imidazolidine 10 and its hydrochloride.
(Rl = -NHCHO, R - -OH) 1. 3H-benzoxazo1-2-one 38.4 cc (0.4 mol) of ethyl chloroformate are added, at a temperature between 0 and 10C, to a 15 solution of 38.4 g (0.35 mol) of o-aminophenol in 150 cc of pyridine. W~len the addition has ended, the reaction mixture is stirred for a further 2 hours and then poured into 1.5 litres of diethyl ether. The precipitate is filtered of-f. The ether in the 20 filtrate is evaporated off on a rotary evaporator.
The residue is heated to 180C in order to distill off the pyridine. After cooling, the residue is recrystallised from ethyl acetate. The melting point of the obtained compound is 136C.

2. 6-Nitro-3H-'benzoxazol-2-one -35 g (0.26 rnol) of the compound obtained in step l are introduced into 300 cc of acetic acid, and l9 cc of nitric acid (specific gravity l.42, 5 70% strength) are added at ambient temperature with stirring. The reaction mi~ture is heated gradually to lO0C and kept at this temperature for l hour.
It is then cooled to 20C and the solid is filtered off and washed with acetic acid and then with diethyl 10 ether. The compound obtained melts at 243~C.
3. 6-Amino-3H-benzoxazol-2-one -A suspension of lO g of the compound obtained in step 2 in 250 cc of ethancl, and l g of 10% palladium-on-charcoal, are introduced into a Parr 15 apparatus under a hydrogen pressure of 30 psi.
After filtering off the catalyst,,the filtrate is evaporated to dryness on a rotary evaporator. The residue is washed wi1,h ethanol. This gives the amine, which is then used in the next step.
0 4. 6-(Imidazo]idin -2-ylidene-amino~-3H-benzoxazol-2-one hydroiodide 13 g (86.7 rnillimols) of the compound obtained in step 3 and 22.2 g of 2-methylthio-2-imidazoline hydroiodide are heated to t:he reflux 25 temperature in lO0 cc of pyridine. The reflux is maintained until the evolution of methanethiol has ceased (about 2-3 hours). When the reaction has ended, the cooled mixture is poured into 1.5 litres of diethyl ether. The gummy residue is washed 3 times with 5 300 cc of diethyl ether and taken up in 100 cc of ethanol. The product i9 filtered off and recrystallised from methanol. Its melting point is 270~-272C.
5. 2-t4-Amino-3-hydroxyphenylimino)-imidazolidine dihydrochloride.
1.~ g of the compound obtained in step 4 are dissolved in the minimum amount of water (120 cc) and the solution is treated with Amberlite resin (Cl) in chloroform. The aqueous phase is evaporated to dryness on a rotary evaporator. The residue is 15 ta~en up in 50 cc of concentrated hydrochloric acid and the mixture is heated at the reflux temperature for about 32 hours. The reaction medium is then evaporated to drynesss on a rotary evaporator and the residue is recrystallised fxom ethanol. The 20 melting point of the obtained compound is 283C~

6. 2-(4-Formylamino-3-hydroxyphenylimino)-imidazolidine hydrochloride~
2.2 g of the compound obtained in step 5 are dissolved in about 70 cc of water. The 25 solution obtained is stirred with a solution of 50 cc of Amberlite L A2 resin in 150 cc of toluene. The aqueous phase is decanted, washed with toluene and evaporated to dryness on a rotary evaporator. The residue is dried in _acuo over P205. This gives 5 2-(4-amino-3-hydroxyphenylimino)~innidazolidine `monohydrochloride.
11 cc of formic acid are introduced into a 100 cc round-bottomed flask and 0.875 cc of acetic anhyride is added at 0C~ The reaction mixture is 10 stirred at 0C for 15 minutes and 2 g of the monohydrochloride obtained as described above are added all at once. The reaction mixture is then stirred at ambient temperature for 30 }ninutes and then poured into diethyl ether. The ether is removed 15 and the residue is washed 3 times with diethyl ether.
The residue is dissolved in ethanol, the solution treated with charcoal and crystallised from a mixture of ethanol/petroleum ether. The product is recrystallised from ethanol. Its melting point 20 is 217C (decomposition).
The compounds of the invention which ~ere prepared by way of examples are shown :in the Table which followsO

TABLE
H

~ NH

Rl Compound R2 Melting _ _ p nt 1 -OH-NHCHO HCl - 226 (dec~
2 ~OH-NHSO2CH3 HC1 - 256 (dec) 3 -O:H-~HCONH2 HC1 - 227 (dec) (CH~)3CH3 -NHCHO-OH ~IC1 - 217 (dec) 6 _ _ ~ HCl -230 231 The compounds of general forznula (I) were studied pharmacologically, more particularly for their action on gastric secretion.
The acute toxicity of the compounds of the 5 invention was determined by intraperitoneal adzninistration to male mice of the CD strain, the toxicity is greater than 100 mg/kg animal body weight.
The effect on gastric activity was determined by the test carried out according to the 10 modified version of Shay's -technique (Gastroenterology lg45, 5, 43) described by Pascaud and Laubie (Arzneim .
Forsch, 1971, 10, 1547).
Male CD rats weighing 200 to 250 g are deprived of solid food :Eor 48 hours before the 15 experiment and are divided up into randomised groups.
The animals receive 4 ml of warm physiological serum orally. They are then immediately anaesthetised with ether. After laparotomy, the gastric contents are evacuated via the duodenum by slightly compressing 20 the stomach, and the pylorus is ligatured. Iznmediately afterwards,the compound to be studied, dissolved in physiological seruzn, is injected subcutaneouslyO
4 hours after liyature of the pylorus, the animals are sacrificed, the oesophagus is ligatured 25 and the stoznach is removed. The gastric contents are collected and centrifuged at 4000 G for 3 minutes~

Any sample containing blood or a solid residue corresponding to a volume of more than 0.6 ml is discarded. The volume is measured and the acidity is evaluated using a solution of NaOH, the 5 strength of which is such that 1 ml corresponds to 5 mg of HCl.
~o titrations are carried out:
1. up to the end point of dimethylaminoazobenzene (Topfer's reagent) at pH 3.5 (t.itration representing the "free" acic~ity).
2. up to the end point of phenolphthalein at pH ~3.5 (titration representing the "total" acidity).
The results are expressed in ~ e~uivalents/
15 4 hours/100 g.
The compounds of the invention reduce the volume and the gastric aci.dity. At a dose of 0.1 mg/kg animal body weight the reduction ranges from 45 to 6~/o .
Furthermore, the compounds of the invention can be active in therapeutic applications in which stimulation of the ~-adrenergic receptors is required, for example, the following applications can be envisaged:

- vasoconstriction at the local levei, in particular nasal decongestion, - orthostatic hypotension of genetic or medicinal origin, 5 - glaucoma, gastric hypersecretion.
The invention consequently includes all types of pharmaceutical compositions containing, as active ingredient, an imidazolidine derivative of 10 general formula (I), or a pharmacologically acceptable acid addition salt thereof, in association with any excipient suitable for oral or parenteral administration.
The compounds of general formula (I) can be 15 presented in the form of tablets, coated tablets, gelatin capsules, ordinary capsules, solutions and susperlsions to be taken orally, injectable solutions, and so on.
~le daily dosage can range from 0~1 to 10 mg 20 of active compound.

Claims

The embodiments of the invention, in which an exclusive privilege or property is claimed, are defined as follows:

1. A process for the preparation of an imidazolidine derivative of the general formula:

(I) wherein R1 represents the hydroxy radical and R2 represents a grouping -NHSO2CH3, -NHCOR' or -NHCONR'R", R' and R" independently of one another representing a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or alternatively R2 represents the hydroxy radical and R1 represents a grouping -NHSO2CH3, -NHCOR' or -NHCONR'R", R' and R"
independently of one another representing a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, and pharmacologically-acceptable acid addition salts thereof, characterised in that (A) in respect of a compound wherein R1 represents the hydroxy radical, p-hydroxyaniline is reacted with 2-methylthioimidazoline or an acid addition salt thereof in an inorganic solvent, to give 2-(4-hydroxyphenylimino)-imidazolidine, which is nitrated with nitric acid to give 2-(4-hydroxy-3-nitro-phenylimino)-imidazolidine; that compound is hydrogenated in the presence of a hydrogen catalyst, to give 2-(3-amino-4-hydroxyphenylimino)-imidazolidine, which is reacted with formic acid in the presence of acetic anhydride, or with methylsulphonyl chloride, or with a compound NaNCO or R'NCO (wherein R' represents an alkyl radical having from 1 to 4 carbon atoms) to obtain an imidazolidine derivative of general formula (I) wherein R1 is the hydroxy radical and R2 is a grouping as hereinbefore specified when R1 is the hydroxy radical, or (B) in respect of a compound wherein R2 represents the hydroxy radical, o-aminophenol is reacted with ethyl chloroformate, the 3H-benzoxal-2-one obtained is nitrated with nitric acid, the nitro group of the resulting compound is reduced with hydrogen in the presence of a hydrogenation catalyst, the 6-amino-3H-benzoxazol-2-one thus obtained is reacted with 2-methylthioimidazoline or an acid addition salt thereof and the resulting compound is acidified to give 2-(4-amino-3-hydroxy-phenylimino)-imidazolidine, which is reacted with formic acid in the presence of acetic anhydride, or with methylsulphonyl chloride, or with a compound NaNCO or R'NCO (wherein R' represents an alkyl radical having from 1 to 4 carbon atoms) to obtain an imidazolidine derivative of general formula (I) wherein R2 is the hydroxy radical and R1 is a grouping as hereinbefore specified when R2 represents the hydroxy radical, and when desired converting an imidazolidine base of general formula (I) thus obtained into a pharmacologically-acceptable acid addition salt.

2. Imidazolidine derivatives of the general formula:

wherein R1 represents the hydroxy radical and R2 represents a grouping -NHSO2CH3, -NHCOR'or -NHCONR'R'', R' and R'' independently of one another representing A hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or alternatively R2 represents the hydroxy radical, and R1 represents a grouping -NHSO2CH3, -NHCOR' or -NHCOR'R'', R' and R'' independently of one another representing a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, and pharmacologically-acceptable acid addition salts thereof, when prepared by the process claimed in claim 1.

3. A process according to claim 1 wherein R1 is a hydroxy radical.

4. Imidazolidine derivatives according to claim 2 wherein R1 represents the hydroxy radical and R2 represents a grouping as specified in claim 2, and pharmacologically-acceptable acid addition salts thereof, when prepared by the process claimed in claim 3.

5. A process according to claim 1 wherein R1 represents the hydroxy radical and R2 represents the grouping -NHCHO, -NHSO2CH3 or -NHCONH2.

6. Imidazolidine derivatives according to claim 2 wherein R1 represents the hydroxy radical and R2 represents the grouping -NHSO2CH3 or -NHCONH2, and pharmacologically-acceptable acid addition salts thereof, when prepared by the process claimed in claim 5.

7. A process according to claim 1 wherein R1 is -OH and R2 is -NHCHO.

8. 2-(3-Formylamino-4-hydroxyphenylimino)-imidazolidine and pharmacologically- acceptable acid addition salts thereof when prepared by the process claimed in claim 7.

9. A process according to claim 1 wherein R1 is -OH and R2 is -NHCONH2.

10. 2-(3-Aminocarbonylamino-4-hydroxyphenylimino)-imidazolidine, and pharmacologically-acceptable acid addition salts thereof, when prepared by the process claimed in claim 9.

11. A process according to claim 1 wherein R1 is -NHCHO and R2 is -OH.

12. 2-(4-Formylamino-3-hydroxyphenylimino)-imidazolidine, and pharmacologically-acceptable acid addition salts thereof, when prepared by the process claimed in claim 11.